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Sex-specific Variation in Signaling Pathways and Gene Expression Patterns in Human Leukocytes in Response to Endotoxin and Exercise

ABSTRACT: While exercise effects on the immune system received increasing attention in recent years, it remains unclear to what extent gender and fluctuations in sex hormones during menstrual cycle influence immunological responses to exercise. Using a previously published microarray data set, we investigated mRNA changes induced through exhaustive exercise (half-marathon; pre-exercise and post-exercise [30 min, 3h, 24h], whole blood culture ± LPS (1h)) with a specific focus on sex differences (women in luteal phase vs men). Inflammation related pathways, TLRs, cytosolic DNA sensing and RIG-I like receptors were differentially activated between sexes in LPS-stimulated cultures. Genes differentially regulated between sexes included TNIP-1, TNIP-3, IL-6, HIVEP1, CXCL3, CCR3, IL-8 and CD69, revealing a bias towards less anti-inflammatory gene regulation in women compared to men. In addition, several genes relevant to brain function (OLIG2, TMEM106B, DDIT4, and KMO) showed differential activation between sexes. Some of these genes (e.g., KMO in women, DDIT4 in both sexes) potentially constitute neuroprotective mechanisms. These data reveal that the exercise-induced change in gene expression might be gender and menstrual cycle phase dependent.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83578 | GEO | 2016/06/22

SECONDARY ACCESSION(S): PRJNA326411

REPOSITORIES: GEO

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Project description:The immunological reaction to exercise has been investigated with increasing intensity in the last 10-20 years, with most human studies performed in male subjects. Recently, gender-specific aspects have received growing attention, but studies carefully monitoring the influence of gender, including the menstrual cycle, are rare. Here, we report gene expression patterns in response to a run at 93% of the individual anaerobic threshold of 9 women with regular menstrual cycles and no use of oral contraceptives who ran both at day 10 (follicular phase, F) and at day 25 (luteal phase, L) of their cycle. 12 male subjects (M) served as controls. The mRNA was pooled group wise and processed on a gene expression microarray encompassing 789 genes, including major genes of the inflammatory and anti-inflammatory reaction. The differences of gene expression between time points t0 (before run) and t1 (after run) were analyzed. Females in L showed a higher extent of regulation than females in F or men. Among those genes which were up-regulated above 1.5 fold change (log2), pro-inflammatory genes were significantly enriched (p=0.033, after Bonferroni correction) in L, while this was not the case in F or M. Conversely, women in L showed a strong trend towards down-regulation of anti-inflammatory genes. Some prominent genes like interleukin (IL)-6 and IL1RN (coding for IL-1 receptor antagonist, also used as IL1RA) were clearly regulated in opposite directions in L as opposed to F and M. In conclusion, women in L showed a distinctly different pattern of gene regulation in response to exercise, compared with women in F or M. The overall direction of gene expression changes of women in L is clearly pro-inflammatory. This finding accentuates a need for careful consideration of the female cyclic phase when investigating women in exercise immunology studies. Our results may also have implications relevant to other forms of stress in females. Keywords: time course, stress response

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Sex-specific Variation in Signaling Pathways and Gene Expression Patterns in Human Leukocytes in Response to Endotoxin and Exercise

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